Reactivating T cell immunity in Wnt-hyperactivated non-small cell lung cancer through a supramolecular droplet of carnosic acid and peptide

The Wnt/β-catenin signaling pathway is renowned for its contribution to the immunosuppressive microenvironment in non-small cell lung cancer (NSCLC). Consequently, inhibiting this pathway has emerged as a promising strategy to enhance immune activation and reinstate T cell responses in cancer treatment. In this study, we initially investigate the metabolic characteristics of Wnt-hyperactivated NSCLC using mass spectroscopic detection in a mouse <i>in-situ</i> model and unveil its significant feature of acid accumulation at tumor sites. Building upon this discovery, we design an acid-sensitive peptide-carnosic acid (CA) supramolecular droplet (Pep1@CA), which leverages the acidic microenvironment characteristic of NSCLC for controlled release. By doing so, we aim to enhance targeting efficiency while minimizing off-target effects. As anticipated, Pep1@CA demonstrates potent tumor-specific inhibition of the Wnt signaling pathway and effectively reactivates T cell immunity in Wnt-hyperactivated NSCLC. Importantly, comprehensive <i>in vivo</i> evaluations reveal significant antitumor efficacy alongside excellent biosafety profiles. Collectively, this study provides a therapeutic strategy with promising clinical translational potential for targeting the Wnt signaling pathway and offers theoretical support for its application in immunotherapy. This innovative approach underscores that targeting pathways beyond traditional immunotherapy can also activate tumor immunity, thereby expanding the potential of cancer immunotherapy.